US4794186A - Thiazolylacetic acid derivative and processes for preparing the same - Google Patents

Thiazolylacetic acid derivative and processes for preparing the same Download PDF

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US4794186A
US4794186A US06/681,252 US68125284A US4794186A US 4794186 A US4794186 A US 4794186A US 68125284 A US68125284 A US 68125284A US 4794186 A US4794186 A US 4794186A
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compound
mixture
oxyimino
pyrrolidon
lower alkyl
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Toyonari Oine
Yoshihisa Yamada
Hiroshi Sugano
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Tanabe Seiyaku Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • This invention relates to a novel thiazolylacetic acid derivative of the formula: ##STR2## wherein R 1 NH-- is amino or a protected amino group, R 2 is hydrogen or lower alkyl, --COOR 3 is carboxy or a protected carboxy group and n is an integer of 2 or 3, or a salt thereof, and processes for preparing the same.
  • the compound (I) or a salt thereof of the present invention is novel and is seful as an intermediate in the synthesis of cephalosporins.
  • a preferred subgenus includes those of the formula (I) in which R 1 is hydrogen, lower alkanoyl such as formyl, acetyl or pivaloyl, mono-, di- or trihalogeno-lower alkanoyl such as chloroacetyl or trifluoroacetyl, lower alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl or tert.-butoxycarbonyl, mono-, di- or trihalogeno-lower alkoxycarbonyl such as 2,2,2-trichloroethoxycarbonyl, substituted or unsubstituted benzyloxycarbonyl such as benzyloxycarbonyl or p-methoxybenzyloxycarbonyl, substituted or unsubstituted phenyl-lower alkyl such as benzyl, p-methoxybenzyl or 3,4-dimethoxybenzyl, or di- or triphen
  • More preferred subgenus includes those of the formula (I) in which R 1 is hydrogen, formyl, acetyl, chloroacetyl, 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl, or trityl; R 2 is hydrogen or methyl; R 3 is hydrogen or ethyl; and n is an integer of 2 or 3.
  • R 1 is hydrogen, formyl, acetyl, chloroacetyl, 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl or trityl
  • R 2 and R 3 are hydrogen and n is an integer of 2.
  • Another preferred subgenus includes those of the formula (I) in which R 1 is hydrogen or trityl, R 2 and R 3 are hydrogen and n is an integer of 2. Most preferred subgenus includes those of the formula (I) in which R 1 , R 2 and R 3 are hydrogen and n is an integer of 2.
  • the structural formula (I) shown above intends to show that the isomeric configuration of the oxyimino group is Z (i.e., syn)-configuration. Although the Z (i.e., syn)-isomers of the invention are preferred, they may coexist with small amount of E (or anti)-isomer.
  • the compound (I) can exist in the form of two optical isomers due to asymmetric carbon atom involved therein, either an optical isomer of the compound (I) or a racemic modification thereof are included within the scope of the present invention.
  • an optical isomer of the compound (I) or a racemic modification thereof are included within the scope of the present invention.
  • the (Z)-(S)-isomer of the compound (I) is preferred.
  • the compound (I) may be prepared by the step(s) of :
  • R 1' NH-- is amino or a protected amino group to give a compound of the formula: ##STR4## wherein R 1' NH--, R 2 , --COOR 3' and n are the same as defined above, or
  • examples of the group represented by R 1' include hydrogen, lower alkanoyl such as formyl, acetyl or pivaloyl, mono-, di- or trihalogenolower alkanoyl such as chloroacetyl or trifluoroacetyl, lower alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl or tert.-butoxycarbonyl, mono-, di- or trihalogeno-lower alkoxycarbonyl such as 2,2,2-trichloroethoxycarbonyl, substituted or unsubstituted benzyloxycarbonyl such as benzyloxycarbonyl or p-methoxybenzyloxycarbonyl, substituted or unsubstituted phenyl-lower alkyl such as benzyl, p-methoxybenzyl or 3,4-dimethoxybenzyl, and di- or triphenyl-lower alkyl such
  • Examples of the reactive residue (X 2 ) include a group of the formula: R 4 SO 2 O-- (wherein R 4 lower alkyl or an unsubstituted or substituted phenyl) (e.g., methylsulfonyloxy, ethylsulfonyloxy, phenylsulfonyloxy, p-tosyloxy) and halogen atom (e.g., chlorine, bromine).
  • R 4 SO 2 O--- wherein R 4 lower alkyl or an unsubstituted or substituted phenyl
  • halogen atom e.g., chlorine, bromine
  • the reaction of the compound (II) with the compound (III) may be accomplished in the presence of an acid acceptor in a solvent.
  • the acid acceptor includes, for example, an organic tertiary amine such as N,N-dimethylaniline, triethylamine or pyridine.
  • Lower alkanol e.g., methanol, ethanol, isopropanol
  • a mixture of said alkanol and water is suitable as the solvent. It is preferred to carry out hhe reaction at a temperature of 10° C. to 80° C.
  • the reaction of the compound (IV) with the compound (V) may also be accomplished in the presence of an acid acceptor in a solvent.
  • the acid acceptor includes, for example, an alkali metal carbonate (e.g., potassium carbonate, sodium carbonate), an alkali metal hydride (e.g., sodium carbonate, sodium carbonate), an alkali metal hydride (e.g., sodium hydride), or an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide).
  • Acetone, tetrahydrofuran, ethyl acetate, dimethylsulfoxide and dimethylformamide are suitable as the solvent. It is preferred to carry out the reaction at a temperature of 10° C. to 80° C.
  • the removal of the protecting group or groups from the compound (I') thus obtained may be conducted by conventional manners such as, for example, hydrolysis, solvolysis, acid treatment or reduction.
  • the protecting group (R 1' ) on the amino group is formyl, acetyl, tert.-butoxycarbonyl, benzhydryl or trityl and the protecting group (R 3' ) on the carboxy group is tert.-butyl or benzhydryl
  • said group or groups may be removed by treating the compound (I') with an acid.
  • Suitable examples of such acid include formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid or hydrogen bromide.
  • This reaction may be conducted with or without a solvent.
  • the solvent are water, methanol, ethanol, acetic acid or dioxane. It is preferred to carry out the reaction at a temperature of -30° C. to 70° C., especially 10° C. to 50° C.
  • the trifluoroacetic acid is used as the acid, it is preferred to carry it out in the presence of anisole.
  • the removal of said protecting group may be conducted by heating the compound (I') in a solvent.
  • a solvent are lower alkanol (e.g., methanol, ethanol), water or a mixture thereof. It is preferred to carry out the reaction at a temperature of 40° C. to 100° C., preferably at 50° C. to 80° C.
  • the removal of said potecting group or groups may be conducted by catalytic hydrogenation of the compound (I') in hydrogen gas in the presence of a catalyst.
  • This catalytic hydrogenation is preferably carried out at a temperature of 0° C. to 100° C., especially 10° C. to 40° C., under atmospheric or increased pressure.
  • Preferred examples of the catalyst include palladium-BaCO 3 , palladium-charcoal and palladium-black. Methanol, ethanol, tetrahydrofuran and water are suitable as the reaction solvent. Further, when the protecting group (R 1' ) on the amino group is trifluoroacetyl, pivaloyl, methoxycarbonyl or ethoxycarbonyl and the protecting group (R 3' ) on the carboxy group is lower alkyl such as methyl or ethyl, said group or groups may be removed by hydrolysis of the compound (I'). The hydrolysis of the compound (I') may be carried out in conventional manners, for example, by treating it with an alkali agent or an acid in a solvent.
  • alkali agent examples include an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide), or an alkali earth metal hydroxide (e.g., calcium hydroxide, ballium hydroxide), and examples of the acid include hydrochloric acid and hydrobromic acid.
  • Lower alkanol e.g., methanol, ethanol
  • dimethylformamide a mixture of said solvent and water are suitable as the solvent. It is preferred to carry out the reaction at a temperature of 10° C. to 80° C. preferably at 20° C. to 60° C.
  • the protecting group (R 1' ) on the amino group is chloroacetyl
  • said group may be removed by treating the compound (I') with thiourea in a solvent.
  • Methanol, ethanol and water are suitable as the solvent. It is preferred to carry it out at a temperature of 20° C. to 80° C., especially 20° C. to 50° C.
  • the starting compound (II) or (V) of the present invention involves two optical isomers due to asymmetric carbon atom involved therein.
  • the compound (I) of the invention in an optically active form can be readily obtained by the use of an optically active isomer of the compound (II) of (V) as the starting material.
  • an optically active resolving agent selected from the group consisting of an optically active tyrosine hydrazide, an optically active ⁇ -methylbenzylamine and an optically active phenylalanine lower alkyl ester to form two diastereoisomeric salts thereof, separating said diastereoisomeric salts from each other by difference in solubility thereof,
  • racemic modification of the compound (I) in which R 1 NH-- is amino group, R 2 is hydrogen, --COOR 3 is carboxy group and n is an integer of 2, i.e., (Z)-2-(2-aminothiazol-4-yl)-2-[((3RS)-2-pyrrolidon-3-yl)oxyimino]acetic acid, can be readily separated into each optical isomers by the steps of reacting said compound with an optically active tyrosine hydrazide to form two diastereoisomeric salts thereof, and separating said diastereoisomeric salts from each other by difference in solubility thereof.
  • the compound (I) in which R 1 NH-- is tritylamino group, R 2 is hydrogen, --COOR 3 is carboxy and n is an integer of 2, i.e., (Z)-2-(2-tritylaminothiazol-4-yl)-2-[((3RS)-2-pyrrolidon-3-yl)oxyimino]acetic acid, can be readily separated into each optical isomers by the steps of reacting said compound with an optically active phenylalanine lower alkyl ester (e.g., methyl ester) or an optically active ⁇ -methylbenzylamine to form two diastereoisomeric salts thereof, and separating said diastereoisomeric salts from each other by difference in solubility thereof.
  • an optically active phenylalanine lower alkyl ester e.g., methyl ester
  • an optically active ⁇ -methylbenzylamine optically active ⁇ -methylbenzylamine
  • said resolving agent is preferably used at an amount of 0.5 to 1.3 moles, especially 0.8 to 1.3 moles, per mole of the racemic modification of the compound (I). It is preferred to carry out the reaction at a temperature of 0° C. to 70° C. in a solvent (e.g., water, a lower alkanol such as methanol or ethanol, a lower alkanone such as acetone, dioxane, tetrahydrofuran or a mixture thereof).
  • a solvent e.g., water, a lower alkanol such as methanol or ethanol, a lower alkanone such as acetone, dioxane, tetrahydrofuran or a mixture thereof.
  • the subsequent separation of the diastereoisomeric salts from each other is carried out by crystallizing the less soluble diastereoisomeric salt, and then collecting said less soluble distereorisomeric salt from the reaction mixture according to a conventional solid-liquid separation technique such as filtration or centrifugation.
  • the less soluble diastereoisomeric salt thus obtained may be, if necessary, subjected to a further treatment such as washing or recrystallization.
  • the less soluble diastereoisomeric salt thus obtained can readily be converted to the optically active compound (I) in free form by treating the thus-obtained diastereoisomeric salt with an acid (e.g., hydrochloric acid, sulfuric acid), or by subjecting the diastereoisomeric salt to salt exchange reaction with an amine (e.g., diethylamine, triethylamine, piperazine, pyridine, N-methylmorpholine), and then treating the resultant amine salt with an acid.
  • an acid e.g., hydrochloric acid, sulfuric acid
  • an amine e.g., diethylamine, triethylamine, piperazine, pyridine, N-methylmorpholine
  • the thus-obtained compound (I) of the present invention in which R 1 NH-- is amino group and/or --COOR 3 is carboxy may be converted to the salt thereof by a conventional method.
  • salts include, for example, metalic salts such as sodium, potassium, calcium or aluminum salts; ammonium salt; salts thereof with amines such as diethylamine or triethylamine; salts thereof with pyridine, piperazine or N-methylmorpholine; salts thereof with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid or nitric acid; salts thereof with organic acids such as benzensulfonic acid, methanesulfonic acid or p-toluenesulfonic acid.
  • the compound (I) of the present invention is useful as an intermediate in the synthesis of cephalosporin compounds.
  • a cephalosporin compound of the formula: ##STR7## wherein R 1 NH--, R 2 and n are the same as defined above, as disclosed in U.S. patent application Ser. No. 516,053 or European Patent Application No. 83304527 is prepared by condensing the compound (I) with a compound of the formula: ##STR8## and, if required, further removing the protecting group from the resultant compound.
  • Said cephalosporin compound shows an excellent antimicrobial activity upon either gram-positive or gram-negative bacteria as compared with known cephalosporin compounds.
  • M.I.C. minimum inhibitory concentration
  • Cefmenoxime [Chemical name: 7 ⁇ -[(Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido]-3-[(1-methyl-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxilic acid] and Ceftazidime [Chemical name: 7 ⁇ -[(Z)-2-(2-aminothiazol-4-yl)-2-(2-carboxyprop-2-yloxyimino)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate] against said microorganism are more than 100 ⁇ g/ml.
  • (6R,7R)-7- ⁇ (Z)-2-(2-aminothiazol-4-yl)-2-[((3S)-2-pyrrolidon-3-yl)oxyimino]acetamido ⁇ -3-(l-pyridiniomethyl)-3-cephem-4-carboxylate exhibits the M.I.C. of 0.39 ⁇ g/ml against Pseudomonas aeruginosa.
  • the starting compound (IV) may be prepared, for example, according to the method described in Tetrahedron., Vol. 34, pages 2233-2243(1978).
  • the starting compound (II) is novel and may be prepared according to the method shown by the following reaction scheme: ##STR9## wherein R 2 , --COOR 3' , X 2 and n are the same as defined above.
  • the compound (II) may be prepared by reacting the compound (VII) with the compound (V) to give the compound (VIII), followed by halogenation thereof.
  • the reaction of the compound (VII) with the compound (V) may be accomplished in the presence of an acid acceptor in a solvent.
  • the acid acceptor include an alkali metal carbonate (e.g., potassium carbonate, sodium carbonate), an alkali metal hydride (e.g., sodium hydride) and an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide).
  • an alkali metal carbonate e.g., potassium carbonate, sodium carbonate
  • an alkali metal hydride e.g., sodium hydride
  • an alkali metal hydroxide e.g., sodium hydroxide, potassium hydroxide
  • Acetone, tetrahydrofuran, ethyl acetate, dimethylsulfoxide and dimethylformamide are suitable as the solvent. It is preferred to carry out the reaction at a temperature of 10° C. to 50° C.
  • the subsequent halogenation may be accomplished in a solvent.
  • a halogenating agent which may be used for this reaction include sulfuryl chloride, chlorine, bromine, N-bromosuccinimide or pyridiniumhydrobromide perbromide. Chloroform, methylene chloride, carbon tetrachloride and 1,2-dichloroethane are suitable as the solvent. It is preferred to carry out the reaction at a temperature of 10° C. to 50° C.
  • optically active isomer of the compound (V) in which X 2 is a group of the formula: R 4 SO 2 O-- (wherein R 4 is the same as defined above) may be prepared, for example, by treating the optically active 3-hydroxy-2-pyrrolidon (cf. Acta Chemica Scandinavica., B 34, pages 731-733, (1980)) with a compound of the formula: R 4 SO 2 X 3 (wherein X 3 is halogen and R 4 is the same as defined above).
  • lower alkyl should be interpreted as referring to alkyl having one to four carbon atoms, alkoxy having one to four carbon atoms and alkanoyl having two to five carbon atoms, respectively.
  • lower alkanol and lower alkanone should be interpreted as referring to alkanol having one to four carbon atoms and alkanone having 3 to 5 carbon atoms.
  • Ethyl (Z)-2-[((3S)-2-pyrrolidon-3-yl)oxyimino]-3-oxo-4-chloro-n-butyrate is thereby obtained as crude product.
  • the crude product thus obtained is dissolved in 20 ml of ethanol, and one g of thiourea and 1.2 g of N,N-dimethylaniline are added thereto.
  • the mixture is stirred at 20° to 25° C. for 2 hours.
  • the mixture is concentrated under reduced pressure to remove solvent.
  • the residue is dissolved in chloroform, and the solution is washed with water and an aqueous sodium bicarbonate solution, successively.
  • the chloroform solution is dried and concentrated under reduced pressure to remove solvent.
  • Crystalline precipitates are collected by filtration, and the crystals are washed with methanol and then dried. 730 mg of (Z)-2-(2-aminothiazol-4-yl)-2-[((3S)-2-pyrrolidon-3-yl)oxyimino]acetic acid are obtained.
  • the residue is dissolved in 25 ml of ethanol, and 2.52 g of N-(2,2,2-trichloroethoxycarbonyl)thiourea and 2.53 g of N,N-dimethylaniline are added thereto.
  • the mixture is stirred at room temperature for 30 minutes and then refluxed for one hour with heating. Then, the mixture is concentrated under reduced pressure to dryness.
  • the residue is dissolved in ethyl acetate, and the solution is washed with water, 5% hydrochloric acid, 5% aqueous sodium bicarbonate solution and an aqueous sodium chloride solution, successively.
  • the ethyl acetate solution is dried and concentrated under reduced pressure to remove solvent.
  • the aqueous layer is adjusted to pH 3 with 10% hydrochloric acid and extracted with a mixture of ethyl acetate and tetrahydrofuran (1:1).
  • the extract is dried and concentrated to dryness under reduced pressure.
  • ether is added to the residue, and the resulting powder is collected by filtration.
  • the minimum inhibitory concentration (MIC, ⁇ g/ml) of a test compound was determined by means of standard agar plate dilution method (based on the standard method of Japan Society of Chemotherapy). Media used in these experiments were Mueller-Hinton agar (MHA; Nissui).
  • mice Ten male mice weighing 20 ⁇ 1 g were used for each dose level. Mice were challenged via the intraperitoneal route with sufficient bacteria to kill all non-treated mice within 24 hours. All bacteria were suspended in 6% mucin. A test compound were administered intramuscularly one hour after the infection. Survival ratios were determined 7 days after the infection. The median effective doses (ED 50 , mg/kg) of the test compound was estimated by the probito analysis.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Cephalosporin Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
US06/681,252 1983-12-21 1984-12-13 Thiazolylacetic acid derivative and processes for preparing the same Expired - Fee Related US4794186A (en)

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JP58242777A JPS60132983A (ja) 1983-12-21 1983-12-21 チアゾ−ル酢酸誘導体及びその製法
JP58-242777 1983-12-21

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EP (1) EP0147181A3 (es)
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US20090299069A1 (en) * 2008-05-27 2009-12-03 Mallinckrodt Inc. Processes and Compounds for the Preparation of Normorphinans
US20100035910A1 (en) * 2007-03-06 2010-02-11 Mallinckrodt Inc. Process for the Preparation of Quaternary N-Alkyl Morphinan Alkaloid Salts
US20100048906A1 (en) * 2006-09-20 2010-02-25 Wang Peter X Preparation of Substituted Morphinan-6-Ones and Salts and Intermediates Thereof
US20110082297A1 (en) * 2007-03-06 2011-04-07 Wang Peter X Process for the Preparation of Quaternary N-Alkyl Morphinan Alkaloid Salts
US9458109B2 (en) 2008-09-03 2016-10-04 Mallinckrodt Llc Substituted berbines and processes for their synthesis

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Cited By (11)

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Publication number Priority date Publication date Assignee Title
US20100048906A1 (en) * 2006-09-20 2010-02-25 Wang Peter X Preparation of Substituted Morphinan-6-Ones and Salts and Intermediates Thereof
US8115002B2 (en) 2006-09-20 2012-02-14 Mallinckrodt Llc Preparation of substituted morphinan-6-ones and salts and intermediates thereof
US20100035910A1 (en) * 2007-03-06 2010-02-11 Mallinckrodt Inc. Process for the Preparation of Quaternary N-Alkyl Morphinan Alkaloid Salts
US20110082297A1 (en) * 2007-03-06 2011-04-07 Wang Peter X Process for the Preparation of Quaternary N-Alkyl Morphinan Alkaloid Salts
US8669366B2 (en) 2007-03-06 2014-03-11 Mallinckrodt Llc Process for the preparation of quaternary N-alkyl morphinan alkaloid salts
US9040726B2 (en) 2007-03-06 2015-05-26 Mallinckrodt Llc Process for the preparation of quaternary N-alkyl morphinan alkaloid salts
US9415044B2 (en) 2007-03-06 2016-08-16 Mallinckrodt Llc Process for the preparation of quaternary N-alkyl morphinan alkaloid salts
US20090299069A1 (en) * 2008-05-27 2009-12-03 Mallinckrodt Inc. Processes and Compounds for the Preparation of Normorphinans
US8148528B2 (en) 2008-05-27 2012-04-03 Mallinckrodt Llc Processes and compounds for the preparation of normorphinans
US9458109B2 (en) 2008-09-03 2016-10-04 Mallinckrodt Llc Substituted berbines and processes for their synthesis
US9856251B2 (en) 2008-09-03 2018-01-02 Mallinckrodt Llc Substituted berbines and processes for their synthesis

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ES8607967A1 (es) 1986-06-01
EP0147181A3 (en) 1986-09-17
KR890000488B1 (ko) 1989-03-18
ES538906A0 (es) 1986-01-01
JPS60132983A (ja) 1985-07-16
EP0147181A2 (en) 1985-07-03
DK614584A (da) 1985-06-22
DK614584D0 (da) 1984-12-20
ES546356A0 (es) 1986-06-01
ES8603848A1 (es) 1986-01-01
KR850004743A (ko) 1985-07-27

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